Tertiary-aminoalkyl derivatives of coumarilic acids and their preparation



Patented Sept. 15, 1953 UNITED STATES PATENT OFFICE TERTIARY-AMINOALKYL DERIVATIVES OF COUMARILIC ACIDS AND THEIR PREP- ARATTON Raymond 0. Clinton, Rensselaer, N. Y., assignor to Sterling Drug Inc., New York, N. poration of Delaware N Drawing. Application Serial No. 191,9

Y., a cor- 0ctober24, 1950,

22 Claims. (Cl. 260-294.3)

where X is O, S or NH, Y is a lower alkylene radical, NRR is a lower aliphatic-like tertiary-amino radical, R is hydrogen or a lower alkyl radical and R is hydrogen, a lower alkyl radical or a lower alkoxy radical.

In the above general formula, when R" and R' represent lower alkyl radicals, they have preferably 1-6 carbon atoms, including such examples as methyl, ethyl, n-propyl, n-butyl, isobutyl, 2-butyl, n-amyl, 3-amyl, n-hexyl, and the like. When R' represents a lower alkoxy radical, it has preferably 1-6 carbon atoms, including such examples as methoxy, ethoxy, n-propoxy, n-butoxy, isobutoxy, Z-amoxy, n-hexoxy, and the like. The lower alkylene radical designated hereinabove as Y has preferably 2-6 carbon atoms and has its two free valence bonds on difierent carbon atoms.

to a new classof comcertain coumarilic acids, of this new class of com- Thus, Y in lud such examples as CH2CH2-, CHzCHzCH2-.

shown above as NRR' compreetc alkaline reagents suitable rolidyl, Z-Inethyhl-pyrrolidyl, 2,5-dimethyl-1- pyr-rolidyl, 4=mor holin L nd h like- I prepared; the compound of my invention by reacting a coumarilic acid halide of the formula U #0 O.-halogen o with a tertiary-amino compound of the formula H-XY-NRR, where R", R', X, Y and have the meanings designated hereinabove. In practicing my invention, I preferably used coumarilic acid chlorines because of the ease of their preparation from the readily available, inexpensive halogenating agent, thionyl chloride. Specific illustrations of this method of preparation are given as follows where X is each of O, S and NH, the resultant products being respectively an ester, a thiol ester and an amide. Reaction of 3-ethylefirn-amoxycoumarilic acid chloride with eachof 2e(2,5:din1ethyl-1-pyrrolidyl) eethanol, 3- l-piperidyl) propanethiol and 4- dimethylaminobuty1amine results respectively in the formation of 2-(2,5-dimethyl-l-pyrro1idyl) ethyl 3-ethyl-fienramoxycoumarilate, 3 (1- piperidyl) propyl 3 ethylefien-amoxythiolcoumarilate and N- (4-dimethylaminobutyl) -3,-ethyl 6-n-amoxycoumarilamide. When prepared in such a manner from the coumarilic acid chlorides, the resultant compounds are obtained in the form of their respective hydrochloride addition salts. The compounds in free base form are conveniently prepar d b neutralizin t e hydroen chloride portion o t e sal s with approp for the purpose, suchas so ium hydro de. sod um ar a dium bicarbonate, etc.

I found it convenient to run th reaction of the coumarilic acid halides With the tertiaryamino alcohols, thiols or amines in the presence of an inert non-Po a l tn such as benzene. toluene, xylene, a petroleum ether fraction, etc. Benzene was preferably used in practicing my inventionbecause of its low cost and ready availability. The reaction can also be run, but less conveniently, in the absence of a solvent. The choice of solvent is not critical.

As already minted out above, the coumarilic acid halides were preferably prepared by treating the acid with thionyl chloride. other H these agents suffer the disadvantages of being more expensive and less conveniently handled than thionyl chloride.

The intermediate coumarilic acids are generally old in the art. Their ease of preparation from the correspoiding coumarins by treatment of the coumarin dibromides with potassium hydroxide is exemplified in the preparation of coumarilic acid from coumarin by Fuson et al. in Organic Syntheses, volume 24, page 33 (1944). In using this method to prepare intermediate coumarilic acids bearing substituents in the 3 and 6 positions, the corresponding coumarin derivative is chosen that bears substituents in the 4 and 7 positions respectively. For example, 3- n-butyl-G-ethoxycoumarilic acid is formed from 4 n-butyl-7-ethoxycoumarin; 3-ethyl-6-n-propoxycoumarilic acid, from 4-ethyl-7-n-propoxycoumarin; etc.

In view of the method used in preparing the compounds of my invention, it was convenient to isolate and use these esters, thiol esters and amides in the form of their water-soluble hydrogen chloride addition salts. It is, of course, understood that other salts will serve the same purpose and are within the scope of my invention. Such salts include the following, which are conveniently formed by treating the free base form of the appropriate ester, thiol ester or amide of my invention with the appropriate non-toxic inorganic or organic acids, for instance I can thus obtain the hydrobromides, the sulfates, the phosphates, the suliamates, the tartrates, the citrates, the succinates, the acetates, the ethanesulionates, the benzoates, the oleates, and the like.

The following examples will further illustrate specific embodiments of the invention.

EXAMPLE 1 A. coumarilic acid chloride A mixture of 76.7 g. (0.47 mole) of coumarilic acid and 328.4 g. (2.76 moles) of thionyl chloride Was heated slowly on a steam bath at approximately 45 C. for two hours. The mixture was then refluxed for two hours and allowed to stand overnight. The thionyl chloride was removed by distillation and the product distilled at 130-133 C. and 9 mm. The yield of coumarilic acid chloride having the formula B. Z-dimeihylaminoethyl coumarilate hydrochloride A solution of 4.5 g. (0.05 mole) of Z-dimethylaminoethanol in 25 ml. of dry benzene was added, with stirring and cooling, to a solution of 9.03 g. (0.05 mole) of coumarilic acid chloride. The reaction mixture, which crystallized during the addition of the amino alcohol, was heated, cooled and absolute ether was added. The product which precipitated was collected by filtration,

washed with absolute ether and recrystallized several times from absolute ethanol-n-hexane, yielding the hydrochloride of 2-dimethylaminoethyl coumarilate as a white crystalline substance, M. P. 187.5-188.8 C. (corn), and having the formula o 0 o CHzCHzN(OHz)z-HC1 Anal-Calcd. for C13H16C1NO32 C, 57.87; H, 5.98; C1, 13.11. Found: C, 58.08; H, 5.96; Cl, 13.22.

2-dimethylaminoethyl coumarilate hydrobromide isformed when the above procedure is carried out, but substituting coumarilic acid bromide (from the acid and PBls) for coumarilic acid chloride.

In addition, other tertiary-aminoalkyl coumarilates in the form of their hydrochlorides which can be prepared by following the directions given above in the reaction of coumarilic acid chloride and 2-dimethylaminoethanol and using the appropriate acid chloride and tertiaryamino-alkanol include the following: G-dimethylaminohexyl coumarilate, 5 diethylamino-2- pentyl 3 methylcoumarilate, 3 (1 pyrrolidyl) propyl B-isobutylcoumarilate, 2-(4-morpholinyl) ethyl 3-n-hexylcoumarilate, 2-di-n-butylaminoethyl coumarilate, 2- (2,5-dimethyl-1-pyrrolidyl) ethyl 3-methylcoumarilate, 2-(3-ethyl-1-piperidyl) ethyl 6-n-hexylcoumarilate, and the like.

EXAMPLE 2 N (3-diethyldminopropyl) coumarilamide hydrochloride A solution of 6.5 g. (0.05 mole) of B-diethylaminopropylamine in 25 ml. of dry benzene was added to a solution of 9.03 g. (0.05 mole) of coumarilic acid chloride in 50 ml. of dry benzene, whereupon a thick gummy paste separated. The reaction mixture was chilled, the solvent removed by decantation, the residual material triturated with ethyl acetate on a steam bath, and the mixture cooled, with crystallization resulting. The crystalline product was filtered, washed with absolute ether and recrystallized several times from absolute ethanol-n-hexane to yield the hydrochloride of N-(3-diethylaminopropyl)coumarilamide, M. P. 81.0-84.0 C. (corn), having the Anal. Calcd. for CmHzsClNzOz: C1, 11.41. Found: Cl, 11.26.

N-(3 diethylaminopropyl) coumarilamide hydrobromide is formed when the above procedure is followed, but using coumarilic acid bromide instead of coumarilic acid chloride.

In addition, other N-(tertiary-aminoalkyD- coumarilamides in the form of their hydrochlorides which can be prepared according to the foregoing procedure using the appropriate acid chloride and tertiary-aminoalkylamine include the following N- (G-dimethylaminohexyl) coumarilamide, N (5-diethylamino 2 pentyl) -3- methylcoumarilamide, N-[3 (1 pyrrolidyl)propyl] -3-isobutylcoumarilamide, N- [2- (l-morpholinyl)ethyl] -3-n-hexylcoumarilamide, N (2-din-butylaminoethyl) coumarilamide, N- [2- (2,5-dimethyl l-pyrrolidyl) ethyl] -6-n-hexy1coumaril- EXAMPLE 3 Z-diethyldminoethyl thiolcoumarilcte hydrochloride This preparation was carried out as in Example 113 except 6.7 g. (0.05 mole) of Z-diethylaminoethanethiol was used in place of 2-dimethylaminoethanol. The resulting product, M. P. 209.5-210.5 C. (corn), has theformula Anal.-Calcd. for C15H20C1NO2S: S, 10.22; C1, 11.30. Found: S, 10.30; Cl, 11.10.

2-diethylaminoethyl thiolcoumarilate in the form of its hydrobromide results when the above procedure is followed, but using coumarilic acid bromide in place of coum-arilic acid chloride.

In addition, other tertiary-aminoalkyl thiolcoumarilates in the form of their hydrochlorides which can be prepared according to the above procedure using the appropriate acid chloride and tertiary-aminoalkanethiol include the following: G-dimethylaminohexyl thiolcoumarilate, diethylamino-2-penty13-methylthiolcoumarilate, 3- l-pyrrolidyl) propyl 3-isobutylthiolcoumarilate, 2-(4 morpholinyl) ethyl 3 n hexylthiolcoumarilate, Z-di-n-butylaminoethyl thiolcoumarilate, 2- (2,5-dimethyl-l-pyrrolidyl) ethyl 6-n-hexylthiolcoumarilate, 2 diethylaminoethyl 6-n-hexoxythiolcoumarilate, 3-(1-piperidyllpropyl 3-n-propyl-6-isobutoxythiolcoumarilate, 3- (2 methyl-l-pyrro-lidyl)propyl 6-n-amoxythiolcoumarilate, 3 diethylaminopropyl 3 ethyl-6- methoxythiolcoumarilate, 2 di n amylamino ethyl 3-methy1-6-n-butoxythiolcoumarilate, and the like.

EXAMPLE 4 3- (Z-methyl-I -piperidyl) propyl coumarilate hydrochloride Anal.Calcd. for C1BH24C1NO3I 7.16; Cl, 10.50. Found: C, 64.12; H,

EXAMPLE 5 e-diethylaminobutyl thiolcoumarilate hydrochloride This thiol ester salt was formed when the procedure illustrated hereinabove as Example 13 is carried out, but using 8.1 g. (0.05 mole) of l-diethylaminobutanethiol instead of 2-dimethyl- C, 63.99; H, 7.07; CI, 10.34.

6 aminoethanol. It melts at 153.1153.9 0. (corn) and has the formula Anal-Calcd. for C17H24ClNO-2S: S, 9.38; Cl, 10.37. Found: S, 9.48; CI, 10.10.

EXAMPLE 6 2- (2,6-dimethyl-1-piperidyl) ethyl coumarilate hydrochloride This ester hydrochloride was prepared following the directions given in Example 13, but using 7.9 g. (0.05 mole) of '2-(2,6-dimethyl-1-piperidyl) ethanol in place of Z-dimethylaminoethanol. The resulting salt was purified further by triturating it twice with acetone and then recrystallized from absolute ethanol and acetone. The product, melting at 207.6-208.8 0. (corn), has the formula 1 (3H3 I /CH-CH2 \O/ "OOQCHZOH2N\ 0112-1101 CH-CH2 Ha Anal.-Calcd. for C18II24C1NO3I C, 03.99; H, 7.16; Cl, 10.50. Found: 0,6404; H, 7.24; Cl, 10.42.

EXAMPLE 7 A. 3,6-dimethylcoumarilzc acid chloride formula CH3 H30 [o 001 B. Z-dimethylam'inocthyl 3,6-dimethylcoumarz'la te hydrochloride This preparation was carried out using the procedure illustrated hereinabove as Example 1B, but using as the reactants 16.7 g. (0.08 mole) of 3,6 -dimethylcoumarilic acid chloride and 7.5 g. (0.08 mole) of Z-dimethylaminoethanol. The resulting product, which melted at 187.4-1883 C. (corn) after recrystallization from isopropanol, has the formula EXAIWPLE 8 3-(2-methyl-1-piperidyl) propyl 3,6-dimethyle co'umarilqte hydrochloride This compound wa prepared following the procedure of Example 73, using 12.8 g. (0.08

mole) of 3-(2-methyl-1-piperidyl)propanol instead of Z-dimethylaminoethanol. It melts at 184.0-185.2 0. (corn) and has the formula 7.71; Cl, 9.69. Found: C, 65.94; H, 7.63; Cl, 9.38.

EXAMPLE 9 A. 4-methyZ-7-n-butoxycoumarin dibromide A solution of 140.3 g. (0.61 mole) of 4-methyl- 7-n-butoxycoumarin [prepared in 61% yield by the reaction in meta-Xylene solution of 7 -hydroxy-4-methylcoumarin and n-butyl benzenesulfonate in the presence of anhydrous potassium carbonate; M. P. 51-52" C.; Bose, et al., Ann. Biochem. Exptl. Med. 5, 1 (1945) give M. P. 51 (3.] in 200 ml. of dry chloroform was placed in a one liter three-necked flask equipped with a Friederick condenser, calcium chloride tube, mechanical stirrer and an addition funnel. A solution of 97.6 g. (0.61 mole) of bromide in 85 ml. of dry chloroform was added dropwise over a period of three hours at room temperature, the reaction mixture being cooled occasionally with an ice bath to prevent the temperature from rising. Excess bromine was destroyed by adding slowly with stirring 200 ml. of a 20% aqueous solution of sodium sulflte. The cloroform layer was separated, washed with water, dried, and the chloroform removed by distilling in vacuo. The resulting light green crystals of 4methyl7-n butoxycoumarin dibromide having the formula CH3 Br 'n'CiH90 \O/C=O was immediate y converted into the related coumarilic acid (see Example 93) B. 3-methyl-6-n-butoxycoumarilic acid In a five liter three-necked flask equipped with a mercury sealed stirrer, 281.3 g. (5.0 moles) of potassium hydroxide was dissolved in 200 m1. of absolute ethanol. This solution was cooled and the 4-methyl-7-n-butoxy-coumarin dibromide of Example 9A was added thereto, and the resulting mixture was refluxed on a steam bath for thirty minutes. One and one-half liters of water were added and the alcohol removed by distilling in vacuo. After the solution had been transferred to a beaker and cooled by adding cracked ice, it was acidified with concentrated hydrochloric acid. The acid, which precipitated as a thick gum and crystallized slowly, was filtered and purified by dissolving it in a solution of 84 g. or sodium bicarbonate in 2000 ml. of water, heating the solution slightly while stirring with decolorizing charcoal, filtering the mixture, acidifying the filtrate with concentrated hydrochloric acid and chilling the acidified solution. There was thus obtained 148.1 g. of crude product, as dark orange crystals, which was recrystallized once from benzene and once from n-heptane, with decolorization using activated charcoal, thereby resulting in about 74.2 g. (44% yield) of 3-methyl-6-n-butoxycoumari1ic acid, M. P. 130.2-131.2 C. (corn), having the formula AnaZ.-Calcd. for 0141-11604: C, 67.72; H, 6.42. Found: C, 67.50; R, 6.46.

In addition, other .coumarilic acids which can be prepared according to the foregoing procedure when the appropriate 7-alkoxycoumarin derivatives are used include: B-ethyl-G-n-hexoxycoumarilic acid, 3-npropyl 6-isobutoxycoumarilic acid, fi-n-amoxycoumarilic 1 acid, 3-ethyl-6- methoxycoumarilic acid, 3-methyl-6-ethoxycoumarilic acid, and the like.

C. B-mcthyl-B-n-butoxycoumarilic acid chloride This preparation was prepared following the procedures described above as Examples 1A and 7A, but using 30 g. (0.11 mole) of 3-methyl-6- n-butoxycoumarilie acid, 40.4 g. (0.39 mole) of thionyl chloride and 200 ml. of dry benzene. The resulting crude residue (after removal of excess thionyl chloride and benzene, addition of more dry benzene, heating the mixture and subsequent removal of the benzene), which had started to'crystallize, was dissolved in 100 ml. of dry benzene. This benzene solution was then divided into two equal portions and used in subsequent'preparations (Examples 9D and 10). Ihe acid chloride has the formula D. Z-dimethylaminoethyl s-mem z-anbutoxycoumarilate hydrochloride This preparation was carried out according to the procedure described above in Example 113, but using a solution of about 17.4 g. (0.065 mole) of 3-methyl6-n-butoxycoumarilic acid chloride in 50 ml. of dry benzene (from Example and 5.8 g. (0.065 mole) of 2-dimethylaminoethanol. The crude crystalline ester hydrochloride, which was recrystallized several times from absolute ethanol, with decolorization using activated charcoal, melts at 158.0-160.0 C. (corn) and has the formula Anal.Calcd. for C1aH2eC1NO4Z C, 60.75; H, 7.37; Cl, 9.96. Found: C, 60.85; H, 7.25; Cl, 9.77.

In addition, other tertiary-aminoalkyl 6-alkoxycoumarilates in the form of their hydrochlorides which can be prepared according to the foregoing procedure using the appropriate acid chloride and tertiary-aminoalkanol include the following: 2-(4-morpholinyl) ethyl 3-ethy1- 6 n hexoxycoumarilate, 3 (2 methyl 1 pyrrolidyDpropyl 3-n-propyl 6 isobutoxycoumarilate, -2-din-amylaminoethyl fin-amoxycoumarilate, 5-diethylamino-2 pentyl 3-ethyl-6- methoxycournarilate; 3-diethylaminopropyl 3- methyl-fi-ethoxycoumarilate, 2-(2,5-dimethyl-1 pyrrolidyl) ethyl 3 methyl 6 n butoxycoumarilate, and the like.

EXAMPLE 10 3-(2-methyZ -1-piperidyl) propyl 3-methyl-6- butofcycoumarilate hydrochloride This ester salt was prepared according to the directions given hereinabove under Example 13, but using a. solution of about 17.4 g. (0.065 mole) of 3-methyl-6-n-butoxycoumarilic acid chloride in 50 ml. of dry benzene (from Example 90) and 10.2 g. (0.065 mole) of 3-(2-methyl-l-piperidyl) propanol. The crude crystalline ester hydrochloride, Which was recrystallized, with decolorization using activated charcoal, until the melting point remained constant at 168.7-169.9 0. (corn). has the formula CH3. CHZLCHQ nc.mo coocmomomN OHg-HOL O \CHCH2 C I'Ha AvwlP-Calcd. for C2aHa4C1NO-1I C, 65.15; H, 8.08; 01, 8.36. Found: C, 65.08; H, 7.83; 01, 8.10.

The compounds of my invention are local anesthetics,

I claim:

1. A compound having the formula where X is a member of the group consisting of O, S and NH, Y is a lower alkylene radical, NRR' is a member of the group consisting of lower dialkylamino, l-piperidyl, (lower alkylated) -lpiperidyl, l-pyrrolidyl, (lower alkylated) -1-pyrrolidyl and 4-morpholinyl, R." is a member of the group consisting of hydrogen and lower alkyl radicals and R' is a member of the group consisting of hydrogen, lower alkyl radicals and lower alkoxy radicals.

2. A compound having the formula 10 O O-Y-NRR where Y is a lower alkylene radical and NRR' is a (lower alkylated)-l-piperidyl radical.

3. A compound having the formula where R" and R are each a lower alkyl radical and Y is a lower alkylene radical. 4. A compound having the formula where R" is a lower alkyl radical, R is a lower alkoxy radical and Y is a lower alkylene radical.

5. A compound having the formula where R and R are each lower alkyl radicals, Y is a lower alkylene radical and NRR' is a (lower alky1ated)1-piperidyl radical.

6. A compound having the formula where R is a lower alkyl radical, R' is a lower alkoxy radical, Y is a lower alkylene radical and NR-R' is a (lower alkylated) -l-piperidyl radical.

7. 3-(Z-methyl-l-piperidyl)propyl coumarilate having the formula CH3 T H-CHa leoocmcmomlv cm ore-0H.

8. 2-dimethylaminoethyl 3,6-dimethylcoumarilate having the formula CH3 O GOOCHzCHzN(CHa)g 9. 2 dimethylaminoethyl 3 methyl butoxycoumarilate having the formula I OH: OIC O O OH2GHzN(CHs)2 l0. 3 (2 methyl- 1' piperidyDpropyl 3,6- dimethylcoumarilate having the formula CH3 CH3 /CHCH2 CH; OOOCH2CHzCHzN CH2 CHr-CH! l1. 3 (2 methyl 1 piperidyDpropyl 3- methyl-fi-n-butoxycoumarilate having the formula C H: CH; I

/CHCH2 CH OHgOHgOHaO GOOOHaCHzOHzN CH2 CHrC Hz 12. A process for the preparation of a compound having the formula 13. A process for the preparation of a compound having the formula where Y is a lower alkylene radical and NRR' is a (lower alkylated) -1-piperidyl radical which comrises reacting the corresponding coumarilic acid chloride with a tertiary-aminoalkanol of the formula HO--Y-NRR'.

141. A process for the preparation of a compound having the formula where R," and R are each lower alkyl radicals and Y is a lower a'ikylene radical, which comprises reacting the corresponding coumarilic acid chloride with a tertiary-aminoalkanol of the formula HO-Y--N(1ower alkyDz.

15. A- process for the preparation of a compound having the formula RII m LC O-YN(lower alkyl):

where R" and R' are each lower alkyl radicals, Y is a lower alkylene radical and NRR' is a (lower a1kylated)-1-piperidyl radical which comprises reacting the corresponding coumarilic acid chloride with a tertiaryaminoalkanol of the formula HO -Y-NRR.

17. A process for the preparation of a compound having the formula m V H I o R 7 N o where R is a lower alkyl radical, R." is a lower alkoxy radical, Y is a lower alkylene radical and NRR' is a (lower allzylatedhl-piperidyl radical which comprises reacting the corresponding coumarilic acid chloride with a tertiary-aminoalkanol of theformula I-IO-Y-NRR'.

18. A process for the preparation of 3-(2- methyl 1 piperidyl) propyl coumarilate, which comprises reacting coumarilic acid chloride with 3- (Z-methyl-l-piperidyl) propanol.

19. A process for the preparation of 2-dimethylaminoethyl 3,6 dimethylcoumarilate, which comprises reacting 3,6-dimethy1coumarilic acid chloride with Z-dimethylaminoethariol.

20. A process for the preparation of 2-dimethylaminoethyl 3 methyl-G-n-butoxycoumarilate, which comprises reacting 3-methyl-6-nbutoxyooumarilic acid chloride with Z-dimethylaminoethanol.

21. A process for the preparation of 3-(2- methyll-piperidyl) propyl 3,6 dimethylcoumarilate', which comprises reacting- 3,6-dimethylcoumarilicfacid chloride with 3-( -rnethyl-1 piperidyl) propanol.

22. A process for the preparation of 3-(2- methyl-l-piperidyl) propyl 3-methyl-6-n-butoxycoumarilate, which comprises reacting 3-methyl- G-n-butoxycournarilie acid chloride with 3-(2- methyl- 1 epiperidyl) propanol. V

RAYMOND 0. CLINTON.

References Cited in the file of this patent UNITED STATES PATENTS Name Date 

1. A COMPOUND HAVING THE FORMULA 